Substitued tetrahydro-1,3,5-triazin-2[1H]-thiones as anti-atherosclerotic agents

ABSTRACT

This invention provides compounds of formula 1 having the structure                    
     wherein 
     R 1 , R 2 , R 3 , R 4 , and R 5  are each independently, hydrogen, halogen, alkyl, cycloalkyl, alkenyl, alkynyl, phenylalkyl, alkoxy, aryloxy, fluoroalkoxy, trifluoromethyl, alkylthio, alkylsulfony, —SCF 3 , nitro, alkylamino, or dialkylamino; 
     R 6  is hydrogen, alkyl, cycloalkyl, or arylalkyl; and 
     R 7  is alkyl, cycloalkyl, or arylalkyl or a pharmaceutically acceptable salt thereof which are useful as antiatherosclerotic agents.

This is a divisional application of prior application Ser. No.08/960,832, filed Oct. 30, 1997 now pending, which application claimsthe benefit of U.S. Provisional Application Ser. No. 60/030,902, filedNov. 14, 1996.

FIELD OF THE INVENTION

This invention is in the field of anti-atherosclerotic agents andspecifically relates to compounds, compositions and methods for treatingatherosclerotic conditions such as dysliproteinimias and coronary heartdisease. This invention specifically relates to substitutedtetrahydro-1,3,5-triazin-2[1H]-thione derivatives that elevate HDLcholesterol concentration and which may be useful for the treatment ofatherosclerotic conditions and coronary heart disease.

BACKGROUND OF THE INVENTION

Numerous studies have demonstrated that both the risk of coronary heartdisease (CHD) in humans and the severity of experimental atherosclerosisin animals are inversely correlated with serum HDL cholesterol (HDL-C)concentrations (Russ et al, Am. J. Med., 11 (1951) 480-483; Gofman etal. Circulation. 34 (1966), 679-697; Miller and Miller, Lancet 1 (1975),16-19; Gordon et al., Circulation, 79 (1989), 8-15; Stampfer et al., N.Engl. J. Med., 325 (1991), 373-381; Badimon et al., Lab. Invest., 60(1989), 455-461). Atherosclerosis is the process of accumulation ofcholesterol within the arterial wall which results in the occlusion, orstenosis, of coronary and cerebral arterial vessels and subsequentmyocardial infarction and stroke. Angiographic studies have shown thatelevated levels of some HDL particles in humans appear to be correlatedto a decreased number of sites of stenosis in the coronary arteries ofhumans (Miller et al., Br. Med. J., 282 (1981), 1741-1744).

There are several mechanisms by which HDL may protect against theprogression of atherosclerosis. Studies in vitro have shown that HDL iscapable of removing cholesterol from cells Picardo et al.,Arteriosclerosis, 6 (1986), 434-441). Data of this nature suggest thatone antiatherogenic property of HDL may lie in its ability to depletetissue of excess free cholesterol and eventually lead to the delivery ofthis cholesterol to the liver (Glomset, J. Lipid Res., 9 (1968),155-167). This has been supported by experiments showing efficienttransfer of cholesterol from HDL to the liver (Glass et al.,Circulation, 66 (Suppl. 1) (1982), 102; McKinnon et al., J. Biol, Chem.,261 (1986), 2548-2552). In addition, HDL may serve as a reservoir in thecirculation for apoproteins necessary for the rapid metabolism oftriglyceride-rich lipoproteins (Grow and Fried, J. Biol Chem.. 2,(1978), 1834-1841; Lagocki and Scanu, J. Biol. Chem., 255 (1980),3701-3706; Schaefer et al., J. Lipid Res., 23 (1982), 1259-1273).Accordingly, agents which increase HDL cholesterol concentrations wouldbe of utility as anti-atherosclerotic agents, useful particularly in thetreatment of dysliproteinimias and coronary heart disease.

PRIOR ART

U.S. Pat. No. 3,505,057 and U.S. Pat. No. 3,505,323 (E.I. DuPont deNemours and Co, Apr. 7, 1970) disclose1-aryl-tetrahydro-s-triazin-2[1H]-thiones and their use as herbicidalagents.

U.S. Pat. No 4,193,994 (Pfizer Inc., Mar. 18, 1980) discloses1-(o-tolyl)-3,5-disubstituted tetrahydro-s-triazin-2[1H]-thiones andtheir use as acaricidal agents.

Zhurnal Obshchei Khimii, Vol. 61, No. 8, (1991), pp. 1870-1873 , Englishtranslation (1992), pp. 1728-1730 (Plenum Publishing Co.), report thesynthesis of 1-aryl-3, 5-di-(tert-butyl)-terahydro-triazin-2[1H]-thioneswith no stated specific utility.

Khim. Geterotsikl, Soedin. (1986), pp. 976-980, reports the mass spectraof 1-aryl-3,5disubstituted-tetrahydro-triazin-2[1H]-thiones with nostated specific utility.

DESCRIPTION OF THE INVENTION

In accordance with this invention, there are provided 1-(arylsubstituted)-3,5-disubstituted tetrahydro-triazin-2[1H]-thiones whichare useful as antiatherosclerotic agents.

More particularly, this invention provides antitherosclerotic agents offormula 1 having the structure

wherein

R¹, R², R³, R⁴, and R⁵ are each independently, hydrogen, halogen, alkylof 1-6 carbon atoms, cycloalkyl of 3-8 carbon atoms, alkenyl of 2-7carbon atoms, alkynyl of 2-7 carbon atoms, phenylalkyl of 7-10 carbonatoms, alkoxy of 1-6 carbon atoms, aryloxy of 7-12 carbon atoms,fluoroalkoxy of 1-6 carbon atoms, trifluoromethyl, alkylthio of 1-3carbon atoms, alkylsulfonyl of 1-3 carbon atoms, —SCF₃, nitro,alkylamino in which the alkylamino moiety has 1-6 carbon atoms, ordialkylamino in which each alkyl group has 1-6 carbon atoms;

R⁶ is hydrogen; and

R⁷ is alkyl of 1-6 carbon atoms, cycloalkyl of 3-8 carbon atoms, orarylalkyl of 7-12 carbon atoms

or a pharmaceutically acceptable salt thereof.

With respect to the above compounds, it is preferred that R¹, R², R³,R⁴, and R⁵ are each, independently, hydrogen, halogen, or alkyl of 1-6carbon atoms.

This invention also provides a method of treating or inhibitingatherosclerosis, cardiovascular disease, or dyslipoproteinimias, andimproving the HDL/LDL cholesterol ratio in a mammal in need thereofwhich comprises administering a compound of formula 1 having thestructure

wherein

R¹, R², R³, R⁴, and R⁵ are each independently, hydrogen, halogen, alkylof 1-6 carbon atoms, cycloalkyl of 3-8 carbon atoms, alkenyl of 2-7carbon atoms, alkynyl of 2-7 carbon atoms, phenylalkyl of 7-10 carbonatoms, alkoxy of 1-6 carbon atoms, aryloxy of 7-12 carbon atoms,fluoroalkoxy of 1-6 carbon atoms, trifluoromethyl, alkylthio of 1-3carbon atoms, alkylsulfonyl of 1-3 carbon atoms, —SCF₃, nitro,alkylamino in which the alkylamino moiety has 1-6 carbon atoms, ordialkylamino in which each alkyl group has 1-6 carbon atoms;

R⁶ is hydrogen, alkyl of 1-6 carbon atoms, cycloalkyl of 3-8 carbonatoms, or arylalkyl of 7-12 carbon atoms; and

R⁷ is alkyl of 1-6 carbon atoms, cycloalkyl of 3-8 carbon atoms, orarylalkyl of 7-12 carbon atoms or a pharmaceutically acceptable saltthereof.

With respect to the above methods, it is preferred that R⁶ is alkyl of1-6 carbon atoms; that R⁶ is alkyl of 1-6 carbon atoms, and R¹, R², R³,R⁴, and R⁵ are each, independently, hydrogen, halogen, or alkyl of 1-6carbon atoms. It is more preferred that R⁶ is methyl.

As used in describing this invention, the terms alkyl, alkenyl, andalkynyl include both straight chain as well as branched moieties. Thisincludes the alkyl portions of substituents such as alkoxy, thioalkyl,alkylsulfinyl, alkylsulfonyl, fluoroalkoxy, and the like. The term haloincludes fluorine, chlorine, bromine, and iodine. Fluoroalkoxy includesmono-, di-, tri-, and polyfluorinated alkoxy moieties such as —OCF₃,—OCH₂F, —OCHF₂, —OCH₂CF₃, and the like. The aryl moiety of the arylalkyland aryloxy substituents include radicals such as benzyl, phenyl andnaphthyl.

As used in describing this invention, the term “compounds of thisinvention” includes the broader description encompassing the formulaused in accordance with the above methods, as well as the narrowerdescription encompassing the formula used in accordance with the abovenovel compounds.

The pharmaceutically acceptable salts are those derived from organic andinorganic acids such as, but not limited to: acetic, lactic, citric,tartaric, succinic, fumaric, maleic, malonic, mandelic, malic,hydrochloric, hydrobromic, phosphoric, nitric, sulfuric,methanesulfonic, toluenesulfonic and similarly known acceptable acids.

The 1-(aryl substituted)-3,5-disubstitutedtetrahydro-triazin-2[1H]thiones of this invention are preferentiallyprepared by reacting an appropriately substituted aromatic thiourea withformaldehyde and an amine (Mannich reaction; see J. Marsh, AdvancedOrganic Chemistry, 3rd Ed,, Wiley-Interscience, NY, page 800) as shownin Scheme 1.

wherein R¹, R², R³, R⁴, R5, R⁶, and R⁷ are as described above forformula 1.

The appropriately substituted aromatic thioureas starting materials areeither available commercially or are known in the art or can be preparedby procedures analogous to those in the literature for known compounds(see J. Marsh, Advanced Organic Chemistry, 3rd Ed., Wiley-Interscience,NY, page 1174).

Representative compounds of this invention were evaluated in an in vivostandard pharmacological test procedure which measured the ability ofthe compounds of this invention to elevate HDL cholesterol levels. Thefollowing briefly describes the procedure used and results obtained.Male Sprague-Dawley rats weighing 200-225 g were housed two per cage andfed Purina Rodent Chow Special Mix 5001-S supplemented with 0.25% cholicacid and 1.0% cholesterol and water ad libitum for 8 days. Each testsubstance was administered to a group of six rats fed the same diet withthe test diet mixed in as 0.005-0.1% of the total diet. Body weight andfood consumption were recorded prior to diet administration and attermination. Typical doses of the test substances were 5-100 mg/kg/day.

At termination, blood was collected from anesthetized rats and the serumwas separated by centrifugation. Total serum cholesterol was assayedusing the Sigma Diagnostics enzymatic kit for the determination ofcholesterol, Procedure No. 352, modified for use with ninety-six wellmicrotiter plates. After reconstitutiton with water the reagent contains300 U/l cholesterol oxidase, 100 U/l cholesterol esterase, 1000 U/lhorse radish peroxidase, 0.3 mmoles/l 4aminoantipyrine and 30.0 mmoles/lp-hydroxybenzene sulfonate in a pH 6.5 buffer. In the reactioncholesterol was oxidized to produce hydrogen peroxide which was used toform a quinoneimine dye. The concentration of dye formed was measuredspectrophotometrically by absorbance at 490 nm after incubation at 25°C. for 30 minutes. The concentration of cholesterol was determined foreach serum sample relative to a commercial standard from Sigma

HDL cholesterol concentrations in serum were determined by separation oflipoprotein classes by fast protein liquid chromatography (FPLC) by amodification of the method of Kieft et al. [J. Lipid Res., 32 (1991),859-866]. Using this methodology, 25 ml of serum was injected ontoSuperose 12 and Superose 6 (Pharmacia), in series, with a column bufferof 0.05 M Tris (2-amino-2-hydroxymethyl-1, 3-propanediol) and 0.15 Msodium chloride at a flow rate of 0.5 mL/min. The eluted sample wasmixed on line with Boehringer-Mannheim cholesterol reagent pumped at 0.2mL/min. The combined eluents were mixed and incubated on line through aknitted coil (Applied Biosciences) maintained at a temperature of 45° C.The eluent was monitored by measuring absorbance at 490 nm and gave acontinous absorbance signal proportional to the cholesterolconcentration. The relative concentration for each lipoprotein class wascalculated as the percent of total absorbance. HDL cholesterolconcentration in serum, was calculated as the percent of totalcholesterol as determined by FPLC multiplied by the total serumcholesterol concentration.

Test compounds were administered at a dose of 100 mg/kg or as indicatedin parenthesis (Table I). The duration of treatment was eight days. Theresults obtained in this standard pharmaceutical test procedure areshown below in Table 1.

TABLE I HDL Cholesterol Level Increase (%) Compound of Example at 100mg/Kg or as indicated Example 1 169 Example 2 369 Example 3 145 Example4 478 (75) Example 5 445 Example 6 78 (75) Example 7 94 (50) Example 8165 (50) Example 9 170 (50) Example 10 98 (50) Example 11 345 (50)Example 12 35 (50) Example 13 67 (50) Example 14 149 (50) Example 15 145(50) Example 16 117 (50) Example 17 275 Example 18 63 (50) Example 19116 (50) Example 20 6 Example 21 73 (50) Example 22 27 (50) Example 23141 (50) Example 24 187 (50) Example 25 64 Example 26 21

The results obtained in this standard pharmacological test procedureshowed that the compounds of this invention raised the concentration ofHDL cholesterol, and are therefore useful for treating or inhibitingatherosclerosis, cardiovascular disease, or dyslipoproteinimias, andimproving the HDL/LDL cholesterol ratio, and several metabolicconditions associated with low concentrations of HDL such as lowHDL-cholesterol levels in the absence of dyslipidemia, metabolicsyndrome, non-insulin dependent diabetes mellitus (NIDMM), familialcombined hyperlipidemia, familial hypertriglyceridemia, and dyslipidemiain peripheral vascular disease (PVD).

The compounds of this invention may be administered orally orparenterally, neat or in combination with conventional pharmaceuticalcarriers. Applicable solid carriers can include one or more substanceswhich may also act as flavoring agents, lubricants, solubilizers,suspending agents, fillers, glidants, compression aids, binders ortablet-disintergrating agents or an encapsulating material. In powders,the carrier is a finely divided solid which is in admixture with thefinely divided active ingredient. In tablets, the active ingredient ismixed with a carrier having the necessary compression properties insuitable proportions and compacted in the shape and size desired. Thepowders and tablets, preferably, contain up to 99% of the activeingredient. Suitable solid carriers include, for example, calciumphosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch,gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose,polyvinylpyrrolidine, low melting waxes and ion exchange resins.

Liquid carriers may be used in preparing solutions, suspensions,emulsions, syrups and elixirs. The active ingredient of this inventioncan be dissolved or suspended in a pharmaceutically acceptable liquidcarrier such as water, an organic solvent, a mixture of both orpharmaceutically acceptable oils or fat. The liquid carrier can containother suitable pharmaceutical additives such as solubilizers,emulsifiers, buffers, preservatives, sweeteners, flavoring agents,suspending agents, thickening agents, colors, viscosity regulators,stabilizers or osmo-regulators. Suitable examples of liquid carriers fororal and parenteral administration include water (particularlycontaining additives as above e.g. cellulose derivatives, preferablysodium carboxymethyl cellulose solution), alcohols (including monohydricalcohols and polyhydric alcohols e.g. glycols) and their derivatives andoils (e.g. fractionated coconut oil and arachis oil). For parenteraladministration the carrier can also be an oily ester such as ethyloleate and isopropyl myristate. Sterile liquid carriers are used insterile liquid form compositions for parenteral administration.

Liquid pharmaceutical compositions which are sterile solutions orsuspensions can be utilized by, for example, intramuscular,intraperitoneal or subcutaneous injection. Sterile solutions can also beadministered intravenously. Oral administration may be either liquid orsolid composition form.

Preferably the pharmaceutical composition is in unit dosage form, e.g.as tablets or capsules. In such form, the composition is subdivided inunit dose containing appropriate quantities of the active ingredient;the unit dosage forms can be packaged compositions, for example packetedpowders, vials, ampoules, prefilled syringes or sachets containingliquids. The unit dosage form can be, for example, a capsule or tabletitself, or it can be the appropriate number of any such compositions inpackage form.

The active compound present in these unit dosage forms of thecomposition may be present in an amount of from about one gram to aboutfifteen grams or more, for single or multiple daily administration,according to the particular need of the patient. The daily dose ofactive compound will vary depending upon the route of administration,the size, age and sex of the patient, the severity of the disease state,and the response to the therapy as traced by blood analyusis and thepatients recovery rate. By initiating the treatment regimen with aminimal daily dose of about one gram, the blood levels of HDL and thepatient sympomatic relief analysis may be used to determine whether alarger dose is indicated. Based upon the data presented above, theprojected daily dose for both human and veterinary use wil be from about10 to about 200 milligrams/Kilogram per day. However, in general,satisfactory results are indicated to be obtained at daily dosages inthe range of from 400 milligrams to about 2000 milligrams, convenientlyadministered in divided doses two to four times a day.

The following examples illustrate the preparation of representativecompounds of this invention.

General Procedures for the preparation of Examples 1-26

Procedure A. To a mixture of the appropriately substituted thiourea(29.4 mmol) in EtOH (20 mL), is added 40% aqueous methylamine (32.3mmol, 1.1 molar eq) and 37% aqueous formaldehyde (64.7 mmol, 2.2 molareq). The solution is refluxed under nitrogen until complete by TLC (10%MeOH/CH₂Cl₂ or 2:1 Hex/EtOAc). The reaction mixture is cooled to roomtemperature and the precipitated product is filtered, washed with 50%aqueous ethanol and recrystallized, if necessary (recrystallizationsolvent provided in parenthesis);

Procedure B. Identical to procedure A except that the solvent is removedunder vacuum and the residue is recrystallized (recrystallizationsolvent provided in parenthesis)

Procedure C. Identical to procedure A except that the reaction is run inwater,

Procedure D. Identical to procedure A except that the solvent is removedunder vacuum and the residue is chromatographed on silica gel elutingwith 20% ethyl acetate in hexane;

Procedure E. Identical to procedure A except that the reaction is run indioxane. The solvent is removed under vacuum and the residue is washedwith water and recrystallized;

Procedure F. Identical to procedure A except that the reaction is run indioxane. The solvent is removed under vacuum and residue ischromatographed on silica gel eluting with dichloromethane;

Procedure G. Identical to procedure A except that the reaction is run indioxane. The reaction mixture is poured into water and extracted withdichloromethane. The extracts are evaporated in vacuo and the residue ischromatographed on silica gel with 30% ethyl acetate in hexane;

Procedure H: Identical to procedure G except that the desired productcrystallizes directly upon concentration of the dichloromethaneextracts.

EXAMPLE 1 1-(4Fluoro-phenyl-5-methyl-tetrahydro-1,3,5-triazin-2(1H)-thione

Prepared in 74% yield according to procedure A described above; whitesolid, m.p. 173-175° C. (EtOH). Anal, Calcd. for C₁₀H₁₂FN₃S: C, 53.31;H, 5.37; N, 18.65. Found: C, 53.30; H, 5.36; N, 18.80.

EXAMPLE 2 5-Methyl-1-phenyl-tetrahydro-1,3,5triazin-2(1 H)-thione

Prepared in 65% yield according to procedure A described above; whitesolid, m.p. 175-176° C. (EtOH). Anal. Calcd for C₁₀,H₁₃N₃S: C, 57.94; H,6.32; N, 20.27. Found: C, 57.72; H, 6.27; N, 20.30.

EXAMPLE 31-(2,6-Dichloro-phenyl)-3-isobutyl-5-methyl-tetrahydro-1,3,5-triazin-2(1H)-thione

Prepared in 73% yield according to procedure B described above; whitesolid, m.p. 133-135° C. (heptane). Anal. Calcd. for C₁₄H₁₉Cl₂N₃S: C,50.60; H, 5.76; N, 12.64. Found: C, 50.43; H, 5.68; N, 12.80.

EXAMPLE 41-(5-Chloro-2-methyl-phenyl-5-methyl-tetrahydro-1,3,5-triazin-2(1H)-thione

Prepared in 76% yield according to procedure A described above; whitesolid, m.p. 171-173° C. (EtOH). Anal. Calcd. for C₁₁H₁₄ClN₃S: C, 51.66;H, 5.52; N, 16.43. Found: C, 51.47; H, 5.51; N, 16.24.

EXAMPLE 5 1-(2,4-Dichloro-phenyl)-5-methyl-tetrahydro-1,3,5-triazin-2(1H)-thione

Prepared in 66% yield according to procedure A described above; whitesolid m.p. 171-173° C. (EtOH). Anal. Calcd. for C₁₀H₁₁ClN₃S: C, 43.49;H, 4.01; N, 15.21. Found: C, 43.27; H, 3.87; N, 15.10.

EXAMPLE 61-(5-Chloro-2-methyl-phenyl)-3-isobutyl-5-methyl-tetrahydro-1,3,5,triazin-2(1H)-thione

Prepared in 57% yield according to procedure B described above; whitesolid, m.p. 110-112° C. (isopropyl ether). Anal. Calcd. for C₁₅H₂₂ClN₃S:C, 57.77; H, 7.11; N, 13.47. Found: C, 57.55; H, 7.13; N, 13.37.

EXAMPLE 7 1-(4-Methoxy-phenyl-5-methyl-tetrahydro-1,3,5-triazin-2(1H)-thione

Prepared in 65% yield according to procedure A described above; whitesolid, m.p. 194° C. (MeOH). Anal. Calcd. for C₁₁H₁₅N₃OS: C, 55.67; H,6.37; N, 17.71. Found: C, 56.04; H, 6.35; N, 17.84. Mass spectrum (PBEI,m/z): 237 [M]⁺

EXAMPLE 8 1-(4-Chloro-phenyl)-5-methyl-tetrahydro-1,3,5-triazin-2(1H)thione

Prepared in 83% yield according to procedure A described above; whitesolid, m.p. 178-179° C. (EtOH). Anal. Calcd. for C₁₀H₁₂ClN₃S: C, 49.68;H, 5.00; N, 17.38. Found: C, 49.75; H, 5.23; N, 17.20. Mass spectrum(PBEI, m/z): 241 [M]⁺

EXAMPLE 9 1-(4-Nitro-phenyl)-5-methyl-tetrahydro-1,3,5-triazin-2(1H)-thione

Prepared in 94% yield according to procedure A described above; yellowpowder, m.p. 170-172° C. (EtOH). Anal. Calcd. for C₁₀H₁₂N₄O₂S: C, 47.61;H, 4.79; N, 22.21. Found: C, 47.43; H, 4.75: N, 22.25. Mass spectrum(EI, m/z): 252 [M]⁺

EXAMPLE 101-(4-Dimethylamino-phenyl)-5-methyl-tetrahydro-1,3,5-triazin-2(1H)-thione

Prepared in 52% yield according to procedure C described above; darkgreen solid, m.p. 173-175° C. (EtOH-H₂O). Anal. Calcd. for C₁₂H₁₈N₄S: C,57.57; H, 7.25; N, 22.38. Found: C, 57.30; H, 7.15; N, 22.06. Massspectrum (EI, m/z): 250 [M]⁺

EXAMPLE 115-Methyl-1-(4-trifluoromethyl-phenyl)-tetrahydro-1,3,5-triazin-2(1H)-thione

Prepared in 64% yield according to procedure A described above; whitesolid, m.p. 163-165° C. (EtOH). Anal. Calcd. for C₁₁H₁₂F₃N₃S: C, 48.03;H, 4.39; N, 15.26. Found: C, 48.03; H, 4.17; N, 15.47. Mass spectrum(EI, m/z): 275 [M]⁺

EXAMPLE 12 5-Methyl-1-(4-methyl-phenyl-tetrahydro-1,3,5-triazin-2(1H)-thione

Prepared in 86% yield according to procedure A described above; whitesolid, m.p. 176-178° C. (EtOH). Anal. Calcd. for C₁₁H₁₅N₃S: C, 59.70; H,6.83; N, 18.99. Found: C, 59.86; H, 6.92; N, 19.38. Mass spectrum (EI,m/z): 221 [MI]⁺

EXAMPLE 13 1.5-Dimethyl-3-phenyl-tetrahydro-1,3,5-triazin-2(1 H)-thione

Prepared in 14% yield according to procedure B described above; whitesolid, m.p. 85-87° C. (isopropyl ether). Anal. Calcd. for C₁₁H₁₅N₃S: C,59.70; H, 6.83; N, 18.89. Found: C, 59.92; H, 6.93; N, 18.75. Massspectrum (PBEI, m/z): 221 [M]⁺

EXAMPLE 141-(5-Chloro-2-methyl-phenyl)-3-ethyl-5-methyl-tetrahydro-1,3,5-triazin-2(1H)-thione

Prepared in 72% yield according to procedure A described above; whitesolid, m.p. 129-131° C. (EtOH). Anal. Calcd. for C₁₃H₁₈ClN₃S: C, 55.01;H, 6.39; N, 14.80. Found: C, 55.12; H, 6.40; N, 14.89. Mass spectrum(PBEI, m/z): 283/285 [M]⁺

EXAMPLE 151-(5-Chloro-2-methyl-phenyl)-3,5-dimethyl-tetrahydro-1,3,5-triazin-2(1H)-thione

Prepared in 85% yield according to procedure A described above; whitesolid, m.p. 157-159° C. (EtOH). Anal. Calcd. for C₂H₁₆ClN₃S: C, 53.42;H, 5.98; N. 15.58. Found: C, 53.41; H, 5.89; N, 15.50. Mass spectrum(PBEI, m/z): {fraction (269/271)}[M]⁺

EXAMPLE 161-(5-Chloro-2-methyl-phenyl)-3-isopropyl-5-methyl-tetrahydro-1,3,5-triazin-2(1H)-thione

Prepared in 42% yield according to procedure D described above; whitesolid, m.p. 113-115° C. (petroleum ether-EtOAc). Anal. Calcd. forC₁₄H₂₀ClN₃S: C, 56.46; H, 6.77; N, 14.11. Found: C, 56.62; H, 6.76; N,14.04. Mass spectrum (EI, m/z): {fraction (297/299)}[M]⁺

EXAMPLE 171-(4-Chloro-2-methyl-phenyl)3,5-dimethyl-tetrahydro-1,3,5-triazin-2(1H)-thione

Prepared in 77% yield according to procedure E described above; whitesolid, m.p. 103-105° C. (isopropyl ether-EtOAc). Anal. Calcd. forC₁₂H₁₆ClN₃S: C, 53.42; H, 5.98; N, 15.58. Found; C, 53.41; H, 5.87; N,15.48. Mass spectrum (EI, m/z): {fraction (269/271)}[M⁺

EXAMPLE 181-(4-Chloro-2-methyl-phenyl)-3-isopropyl-5-methyl-tetrahydro-1,3,5-triazin-2(1H)-thione

Prepared in 26% yield according to procedure D described above; whitesolid, m.p. 105-107° C. (petroleum ether-EtOAc). Anal. Calcd. forC₁₄H₂₀ClN₃S: C, 56.46; H, 6.77; N, 14.11. Found: C, 56.50; H, 6.84; N,14.15. Mass spectrum (EI, m/z): {fraction (297/299)}[M]⁺

EXAMPLE 191-(4-Chloro-2-methyl-phenyl)-3-ethyl-5-methyl-tetrahydro-1,3,5-triazin-2(1H)-thione

Prepared in 31% yield according to procedure D described above; whitesolid, m.p. 90-92° C. ( petroleum ether-EtOAc). Anal. Calcd. forC₁₃H₁₈ClN₃S: C, 55.01; H, 6.39; N, 14.81. Found: C, 55.16; H, 6.35; N,14.94. Mass spectrum (EI, m/z): {fraction (283/285)}[M]⁺

EXAMPLE 201-(4-Chloro-2-methyl-phenyl)-3-isobutyl-5-methyl-tetrahydro-1,3,5-triazin-2(1H)-thione

Prepared in 46% yield according to procedure D described above; whitesolid, m.p. 82-84° C. (petroleum ether-EtOAc). Anal. Calcd. forC₁₅H₂₂ClN₃S: C, 57.77; H, 7.1 1; N, 13.47. Found: C, 57.92; H, 7.15; N,13.48. Mass spectrum (EI, m/z): {fraction (311/313)}[M]⁺

EXAMPLE 211-(5-Chloro-2-methyl-phenyl)-5-ethyl-3-methyl-tetrahydro-1,3,5-triazin-2(1H)-thione

Prepared in 64% yield according to procedure B described above; whitesolid, m.p. 93-95° C. (isopropyl ether-EtOAc). Anal. Calcd. forC₁₃H₁₈ClN₃S: C, 55.01; H, 6.39; N, 14.81. Found: C, 54.72; H, 6.33; N,14.69. Mass spectrum (El, m/z): {fraction (283/285)}[M]⁺

EXAMPLE 221-(5-Chloro-2-methyl-phenyl)-5-isopropyl-3-methyl-tetrahydro-1,3,5-triazin-2(1H)-thione

Prepared in 59% yield according to procedure B described above; whitesolid, m.p. 83-85° C. (isopropyl ether). Anal. Calcd. for C₁₄H₂₀ClN₃S:C, 56.46; H, 6.77; N, 14.11. Found: C, 56.27; H, 6.69; N, 14.07. Massspectrum (PBE, m/z): {fraction (297/299)}[M]⁺

EXAMPLE 231-(2,6-Dimethyl-phenyl)-3,5dimethyl-tetrahydro-1,3,5-triazin-2(1H)-thione

Prepared in 64% yield according to procedure B described above; whitesolid, m.p. 121-123° C. (isopropyl ether). Anal. Calcd. for C₁₃H₁₉N₃S:C, 62,61; H, 7.68; N, 16.85. Found: C, 62.30; H, 7.76; N, 16.90.

EXAMPLE 245-tert-Butyl-1-(5-chloro-2-methyl-phenyl)-3-methyl-tetrahydro-1,3,5,-triazin-2(1H)-thione

Prepared in 53% yield according to procedure F described above; whitesolid, m.p. 130-132° C. (dichloromethane). Anal. Calcd. for C₁₅H₂₂ClN₃S:C, 57.77; H, 7.11; N, 13.47. Found: C, 57.84; H, 7.23; N, 13.54. Massspectrum (EI, m/z): {fraction (311/313)}[M]⁺

EXAMPLE 255-Benzyl-1-(5-chloro-2-methyl-phenyl)-3-methyl-tetrahydro-1,3,5-triazin-2(1H)-thione

Prepared in 52% yield according to procedure G described above; whitesolid, m.p. 148-149° C. (hexane-EtOAc). Anal. Calcd. for C₉H₂₂ClN₂S: C,62.50; H, 5.83; N, 121.15. Found: C, 62.27; H, 5.80; N, 11.98. Massspectrum (EI, m/z): 345 [M]⁺

EXAMPLE 261,5-Dibenzyl-3-(5-chloro-2-methyl-phenyl)-tetrahydro-1,3,5-triazin-2(1H)-thione

Prepared according to procedure H described above; white solid, m.p.202-203° C. (dichloromethane). Anal. Calcd. for C₁₈H₂₀ClN₃S: C, 68.31;H, 5.73; N, 9.96. Found: C, 68.10; H, 5.60; N, 9.68. Mass spectrum: (EI,m/z): 421 [M]⁺

What is claimed is:
 1. A method of treating or inhibitingatherosclerosis, cardiovascular disease, or dyslipoproteinimias in amammal in need thereof which comprises administering to said mammal aneffective amount of a compound of formula 1 having the structure

wherein R¹, R², R³, R⁴, and R⁵ are each independently, hydrogen,halogen, alkyl of 1-6 carbon atoms, cycloalkyl of 3-8 carbon atoms,alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, phenylalkyl of7-10 carbon atoms, alkoxy of 1-6 carbon atoms, aryloxy of 7-12 carbonatoms, fluoroalkoxy of 1-6 carbon atoms, trifluoromethyl, alkylthio of1-3 carbon atoms, alkylsulfonyl of 1-3 carbon atoms, —SCF₃, nitro,alkylamino in which the alkylamino moiety has 1-6 carbon atoms, ordialkylamino in which each alkyl group has 1-6 carbon atoms; R⁶ ishydrogen, alkyl of 1-6 carbon atoms, cycloalkyl of 3-8 carbon atoms, orarylalkyl of 7-12 carbon atoms; and R⁷ is alkyl of 1-6 carbon atoms,cycloalkyl of 3-8 carbon atoms, or arylalkyl of 7-12 carbon atoms or apharmaceutically acceptable salt thereof.
 2. The method according toclaim 1, wherein R⁶ is alkyl of 1-6 carbon atoms.
 3. The methodaccording to claim 2, wherein R¹, R², R³, R⁴, and R⁵ are each,independently, hydrogen, halogen, or alkyl of 1-6 carbon atoms.
 4. Themethod according to claim 3, wherein R⁶ is methyl.
 5. The methodaccording to claim 1 in which the compound administered is selected fromthe group consisting of1-(4-chloro-2-methyl-phenyl)-3-isopropyl-5-methyl-tetrahydro-1,3,5-triazin-2(1h)-thione,1-(4-chloro-2-methyl-phenyl)-3-ethyl-5-methyl-tetrahydro-1,3,5-triazin-2(1h)thione,1-(4-chloro-2-methyl-phenyl)-3-isobutyl-5-methyl-tetrahydro-1,3,5-triazin-2(1h)-thione,1-(5-chloro-2-methyl-phenyl)-5-ethyl-3-methyl-tetrahydro-1,3,5-triazin-2(1h)-thione,1-(5-chloro-2-methyl-phenyl)-5-ethyl-3-methyl-tetrahydro-1,3,5-triazin-2(1h)-thione,1-(5-chloro-2-methyl-phenyl)-5-isopropyl-3-methyl-tetrahydro-1,3,5-triazin-2(1h)-thione, 1-(2,6-dimethyl-phenyl)-3,5-dimethyl-tetrahydro-1,3,5-triazin-2(1 h)-thione,5-tert-butyl-1-(5-chloro-2-methyl-phenyl)-3-methyl-tetrahydro-1,3,5-triazin-2(1 h)-thione,5-benzyl-1-(5-chloro-2-methyl-phenyl)-3-methyl-tetrahydro-1,3,5-triazin-2(1 h)-thione, and1,5-dibenzyl-3-(5-chloro-2-methyl-phenyl)-tetrahydro-1, 3,5-triazin-2(1h)-thione, or a pharmaceutically acceptable salt of thereof.
 6. A methodof increasing HDL cholesterol levels in a mammal in need thereof, whichcomprises administering to said mammal an effective amount of a compoundof formula 1 having the structure

wherein R¹, R², R³, R⁴, and R⁵ are each independently, hydrogen,halogen, alkyl of 1-6 carbon atoms, cycloalkyl of 3-8 carbon atoms,alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, phenylalkyl of7-10 carbon atoms, alkoxy of 1-6 carbon atoms, aryloxy of 7-12 carbonatoms, fluoroalkoxy of 1-6 carbon atoms, trifluoromethyl, alkylthio of1-3 carbon atoms, alkylsulfonyl of 1-3 carbon atoms, —SCF₃, nitro,alkylamino in which the alkylamino moiety has 1-6 carbon atoms, ordialkylamino in which each alkyl group has 1-6 carbon atoms; R⁶ ishydrogen, alkyl of 1-6 carbon atoms, cycloalkyl of 3-8 carbon atoms, orarylalkyl of 7-12 carbon atoms; and R⁷ is alkyl of 1-6 carbon atoms,cycloalkyl of 3-8 carbon atoms, or arylalkyl of 7-12 carbon atoms or apharmaceutically acceptable salt thereof.
 7. A method of treating acondition associated with low levels of HDL cholesterol selected fromthe group consiting of metabolic syndrome, non-insulin dependentdiabetes mellitus, familial combined hyperlipidemia, or familialhypertriglyceridemia in a mammal in need thereof, which comprisesadministering to said mammal an effective amount of a compound offormula 1 having the structure

wherein R¹, R², R³, R⁴, and R⁵ are each independently, hydrogen,halogen, alkyl of 1-6 carbon atoms, cycloalkyl of 3-8 carbon atoms,alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, phenylalkyl of7-10 carbon atoms, alkoxy of 1-6 carbon atoms, aryloxy of 7-12 carbonatoms, fluoroalkoxy of 1-6 carbon atoms, trifluoromethyl, alkylthio of1-3 carbon atoms, alkylsulfonyl of 1-3 carbon atoms, —SCF₃, nitro,alkylamino in which the alkylamino moiety has 1-6 carbon atoms, ordialkylamino in which each alkyl group has 1-6 carbon atoms; R⁶ ishydrogen, alkyl of 1-6 carbon atoms, cycloalkyl of 3-8 carbon atoms, orarylalkyl of 7-12 carbon atoms; and R⁷ is alkyl of 1-6 carbon atoms,cycloalkyl of 3-8 carbon atoms, or arylalkyl of 7-12 carbon atoms or apharmaceutically acceptable salt thereof.
 8. A pharmaceuticalcomposition which comprises a compound of formula 1 having the structure

wherein R¹, R², R³, R⁴, and R⁵ are each independently, hydrogen,halogen, alkyl of 1-6 carbon atoms, cycloalkyl of 3-8 carbon atoms,alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, phenylalkyl of7-10 carbon atoms, alkoxy of 1-6 carbon atoms, aryloxy of 7-12 carbonatoms, fluoroalkoxy of 1-6 carbon atoms, trifluoromethyl, alkylthio of1-3 carbon atoms, alkylsulfonyl of 1-3 carbon atoms, —SCF₃, nitro,alkylamino in which the alkylamino moiety has 1-6 carbon atoms, ordialkylamino in which each alkyl group has 1-6 carbon atoms; R⁶ ishydrogen; and R⁷ is alkyl of 1-6 carbon atoms, cycloalkyl of 3-8 carbonatoms, or arylalkyl of 7-12 carbon atoms or a pharmaceuticallyacceptable salt thereof and a pharmaceutical carrier.